Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia.

Autor: Lu Y; Drug Discovery Biology and Neuroscience & Mental Health Therapeutic Program Area, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia., Hatzipantelis CJ; Olson Lab, Department of Chemistry, University of California, Davis, California, USA., Langmead CJ; Drug Discovery Biology and Neuroscience & Mental Health Therapeutic Program Area, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.; Neuromedicines Discovery Centre, Monash University, Parkville, Australia.; Phrenix Therapeutics, Parkville, Australia., Stewart GD; Drug Discovery Biology and Neuroscience & Mental Health Therapeutic Program Area, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.; ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.; Neuromedicines Discovery Centre, Monash University, Parkville, Australia.; Phrenix Therapeutics, Parkville, Australia.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Jul; Vol. 181 (14), pp. 2095-2113. Date of Electronic Publication: 2023 Sep 26.
DOI: 10.1111/bph.16221
Abstrakt: Schizophrenia remains a sizable socio-economic burden that continues to be treated with therapeutics based on 70-year old science. All currently approved therapeutics primarily target the dopamine D 2 receptor to achieve their efficacy. Whilst dopaminergic dysregulation is a key feature in this disorder, the targeting of dopaminergic machinery has yielded limited efficacy and an appreciable side effect burden. Over the recent decades, numerous drugs that engage non-dopaminergic G protein-coupled receptors (GPCRs) have yielded a promise of efficacy without the deleterious side effect profile, yet none have successfully completed clinical studies and progressed to the market. More recently, there has been increased attention around non-dopaminergic GPCR-targeting drugs, which demonstrated efficacy in some schizophrenia symptom domains. This provides renewed hope that effective schizophrenia treatment may lie outside of the dopaminergic space. Despite the potential for muscarinic receptor- (and other well-characterised GPCR families) targeting drugs to treat schizophrenia, they are often plagued with complications such as lack of receptor subtype selectivity and peripheral on-target side effects. Orphan GPCR studies have opened a new avenue of exploration with many demonstrating schizophrenia-relevant mechanisms and a favourable expression profile, thus offering potential for novel drug development. This review discusses centrally expressed orphan GPCRs: GPR3, GPR6, GPR12, GPR52, GPR85, GPR88 and GPR139 and their relationship to schizophrenia. We review their expression, signalling mechanisms and cellular function, in conjunction with small molecule development and structural insights. We seek to provide a snapshot of the growing evidence and development potential of new classes of schizophrenia therapeutics. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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